Recently, it has been demonstrated that a number of novel thalidomide analogs possess anti-cancer properties due to their T cell co-stimulatory, anti-angiogenic and/or anti-inflammatory effects. Based on such effects, a class of thalidomide analogs known as Immunomodulatory Drugs (IMiDs™) have recently entered into phase I clinical trials for the treatment of a number of cancers. The lead IMiD CC-5013 (referred to clinically as REVIMID™) is now entering phase III clinical trials for multiple myeloma and metastatic melanoma, while CC-4047 (ACTIMID™) is currently under investigation in phase I/II and II trials for multiple myeloma and prostate cancer, respectively. The other group of compounds, classified as Selective Cytokine Inhibitory Drugs (SelCIDs™), do not co-stimulate T cells, but have anti-inflammatory and anti-angiogenic properties. Moreover, a subset of SelCIDs has been found to posses direct anti-tumor activity bothin vitroandin vivo. This minireview highlights the various mechanisms of action associated with these compounds and their subsequent clinical development. The enhanced efficacy and lower side-effect profiles of the analogs in comparison to thalidomide make the use of these agents very attractive as novel anti-cancer agents.